Drying processes, such as the drying of liquids and their conversion into solid materials, are standard operations in various industries including the pharmaceutical and food industries. Common types of dryers include tray dryers, spray dryers, fluid bed dryers, vacuum dryers, belt dryers, and freeze dryers.
Freeze drying is a drying method which has gained substantial importance in particular in the manufacture of drug products for injectable use comprising biotechnology-derived active ingredients. One of the reasons for this is that freeze drying allows the gentle manufacturing of sensitive products even under aseptic conditions. Freeze drying, however, is a complex process usually consisting of three major steps: freezing, primary drying and secondary drying. During freezing, the water will form ice crystals, and solutes will be confined to the interstitial region in a liquid, glassy or crystalline state. In the course of primary drying, the pressure on the product is reduced and applied heat results in the sublimation of the ice. Primary drying is complete when the ice crystals have been removed. At this stage, water is still absorbed onto the surface of a cake resulting from the solutes. In many cases the moisture level is too high and final products may not have the desired stability. Therefore the moisture desorption is usually accomplished in a secondary drying step by increasing the temperature and reducing the pressure.
The sequential approach with different impact on the product performance considering also the formulation requires substantial effort for understanding and control. In a FDA Guidance for Industry, the concept of “Process Analytical Technology” (PAT), a framework for innovative pharmaceutical manufacturing and quality assurance, was established (Guidance for Industry: PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, published 29 Sep. 2004). The initiative is based on process understanding, acknowledgement of process variability and risk-based understanding to increase quality, reduce loss and obtain greater control of the manufacturing process.
Various PAT-tools are known. Batch methods comprise pressure rise analysis, spectroscopy based measurements like tuneable diode laser absorption spectroscopy, mass spectrometry to determine the relative amounts of the compounds in the freeze-dryer atmosphere, electric moisture sensors, pirani/capacitance manometry. Single vial measurement methods comprise temperature probes, conductivity probes, microbalances, NIR-spectroscopy, Raman-spectroscopy and offline analytics after sampling.
The product temperature profile is one of the most critical parameters in drying, in particular freeze-drying. The collapse temperature or glass transition temperature of the formulation at different stages of the process at different water content may reflect an upper acceptable limit of the product temperature. The product temperature also defines the endpoints of primary and secondary drying. The product temperature is affected by various different parameters such as resistance of the material to heat and vapour flow, the formulation or the position in the freeze-dryer.
Product temperature monitoring during a freeze-drying cycle is traditionally performed using either thin wire thermocouples or resistance thermal detectors. However, the invasive product temperature measurements performed with these detectors in a single vial are not representative for the entire batch due to variations in the nucleation and freezing behaviour of the solution containing the probe. The vials tend to show a lower degree of supercooling than the surrounding vials and therefore form fewer and larger ice crystals which finally results in lower product resistance and shorter drying time relative to the rest of the batch. While these difference may be inconsequential in the laboratory, the sterile and particle-free environment in manufacturing leads to substantially higher supercooling of the solution, resulting in larger differences between vials with and vials without temperature sensors. Accordingly, the existing temperature sensors have a substantial impact on the structure and the drying behaviour of the products as they strongly impact the ice formation process. Therefore, the information gained from known conventional temperature sensors is limited in its usefulness for process development and control. Due to individual wiring of each sensor as a parallel connection handling with numerous wires can become difficult and container closure can be negatively affected. Furthermore, in samples of limited space or volume they cannot be applied and multiple measuring points in one sample or vial can hardly be achieved. Overall sensitivity and precision of these standard temperature sensors are rather limited.
In US 2003/0116027 A1 a method for monitoring a freeze-drying process in a freeze dryer holding one or more samples is described, which uses an optical fiber assembly to monitor the temperature of a sample. The monitoring system is operated by extrinsic spectroscopy. Radiation is generated in a radiation analyzer and transmitted to the sample in the freeze dryer via optical fibers. The incident radiation is directed onto the sample, whereupon radiation diffusely reflected from the sample is collected by the optical fiber and carried back to the radiation analyzer to be analyzed spectrally. For this purpose each optical fiber is guided through a wall portion of a vacuum chamber of the freeze dryer to reach a sample container. The optical fiber is arranged outside the container, the distal end of the fiber being arranged close to or against a wall portion of the container. The container is made of a material that is transparent to radiation in the relevant wavelength range. Also the end of the optical fiber can be arranged in direct contact with the probe. In a specific embodiment, the device is operated with near infrared radiation (NIR) in the range corresponding to the wavelengths from about 700 to 2,500 nm.
However, this monitoring device has several drawbacks. Most importantly, it requires an interaction of the radiation with the sample material which is to be dried. Hence, the material can only be contained in vessels which are transparent to the radiation that is used (i.e. NIR). Secondly, in order to monitor multiple samples within the dryer simultaneously, the number of fibers and optical channels would have to be multiplied as well, thus resulting in a complex and expensive monitoring system. Thirdly, the method is not particularly sensitive and, for example, does not appear to be suitable to detect the small differences in temperature between different vials located in various positions in a dryer during a drying cycle.
It is therefore an object of the present invention to provide a monitoring device for a dryer which overcomes at least one of the disadvantages associated with prior art monitoring systems and devices. It is a further object of the invention to provide an improved monitoring device suitable for a freeze dryer.
In a further aspect, it is an object of the invention to provide a monitoring device for dryers, in particular for freeze dryers, which is easy to handle, requires only a small number of components and is cost-effective.
A further object is to provide a monitoring device for dryers which is capable of simultaneously monitoring the temperature profiles of a plurality of samples.
A yet further object is to provide a monitoring device for a dryer which allows for a better control of the manufacturing process and enhanced quality assurance during drying, in particular freeze-drying, in particular of pharmaceutical products.
It is a further object of the invention to provide a monitoring device for a dryer that ensures a high sensitivity and sampling rate.
It is a yet further object to provide a monitoring device for a dryer which allows the monitoring of further physical parameters in addition to temperature.
In a further aspect, it is an object of the invention to provide a dryer which allows the monitoring of a drying process and overcomes one or more of the disadvantages of known dryers.
It is also an object to provide an improved method for drying materials, in particular for freeze drying pharmaceutical products.
Further objects will become apparent from the description of the invention and the patent claims.